The present invention relates to 5-hydroxybenzo[b]thiophene-3-carboxylic acid derivatives which are key starting materials for producing compounds useful in the field of pharmaceuticals.
5-Hydroxybenzo[b]thiophene-3-carboxylic acid derivatives of the general formula (I): 
wherein R is hydrogen or a hydroxy-protecting group are important starting materials in the synthesis of pharmacologically active compounds. For example, a compound of the formula (I) is essential in the synthesis of benzothiophenecarboxamide derivatives of the general formula (VI): 
wherein R is as defined above and X is hydrogen or alkyl. The benzothiophenecarboxamide derivatives are specific antagonists of PGD2 and known to be useful as a drug in the treatment of various diseases related to mast cell dysfunction caused by excessive production of PGD2, for example, systemic mastocytosis, disorder of systemic mast cell activation, tracheal contraction, asthma, allergic rhinitis, allergic conjunctivitis, urticaria, injury due to ischemic reperfusion, inflammation, and atopic dermatis (WO97/00853, PCT/JP97/04527 (WO98/25919)). Among compounds of the formula (VI), a compound wherein OR is 5-hydroxy and X is hydrogen (hereinafter, referred to as xe2x80x9cCompound Axe2x80x9d) has especially high antagonistic effect on PGD2, showing an excellent anti-nasal occlusion activity, and is contemplated to be a promising drug for treating nasal occlusion.
A process for preparing the above-mentioned compound is illustrated by the following reaction scheme (WO98/25919): 
In order to clinically apply Compound A widely, it is essential to establish a process for preparing a starting material, the compound (I), which process is safe, efficient and industrially applicable.
However, it is difficult to synthesize benzothiophene derivatives having 5-hydroxyl group like the compound (I) and there have been no methods industrially applicable so far. The existing methods involve various complicated processes and are inefficient and of low yield. For example, there have been methods wherein 5-acetoxybenzo[b]thiophene is brominated to yield 3-bromo-5-acetoxybenzo[b]thiophene, which in turn is re-protected at the 5-acetoxy group with a benzyl group to yield 3-bromo-5-benzyloxybenzo[b]thiophene, which is followed by metallization with magnesium, introduction of carbon dioxide and removal of the benzyl group (J. Chem. Soc. (C). 1967, 1899-1905); or 5-bromobenzo[b]-thiophene is subjected to Friedel-Crafts reaction to yield 3-acetyl-5-bromobenzo[b]thiophene, which is followed by oxidation with sodium hypochlorite to yield 5-bromobenzo[b]thiophene-3-carboxylic acid (Nippon-Kagaku Zasshi vol. 86, No. 10, 1067-1072(1965), J. Chem. Soc. (C). 1967, 2084-2089). 5-Hydroxybenzo[b]thiophene-3-carboxylic acid or 5-acetoxybenzo[b]thiophene-3-carboxylic acid are then synthesized starting from the reaction products above. However, the starting material such as 5-hydroxybenzo[b]thiophene or 5-bromobenzo[b]thiophene is not commercially available and had to be synthesized from an appropriate reagent (e.g., J. Am. Chem. Soc., 57, 1611(1935), J. Heterocyclic Chem., 25, 1271(1988)) in all cases, which have made the synthetic process longer and complex.
The present invention solves the problems of the existing methods and provides a method for the preparation of the compounds of the formula (I), which method is industrially applicable, efficient and safe.
Thus, the present invention provides a process for preparing a compound of the formula (I): 
wherein R is hydrogen or a hydroxy-protecting group, or a reactive derivative thereof comprising subjecting 4-mercaptophenol to reactions for introduction of a propargyl group and protection of hydroxyl group to yield a compound of the formula (II): 
wherein R1 is a hydroxy-protecting group; oxidizing the compound (II) to yield a compound of the formula (III): 
wherein R1 is a hydroxy-protecting group; subjecting the compound (III) to thermal rearrangement reaction to yield a compound of the formula (IV): 
wherein R1 is as defined above; and subjecting the compound (IV) to stepwise oxidation of hydroxymethyl group and optionally deprotection.
The present invention also provides a process for preparing a compound of the formula (I): 
wherein R is hydrogen or a hydroxy-protecting group or a reactive derivative thereof comprising subjecting 5-hydroxybenzo[b]thiophene to a protecting reaction to yield a compound of the formula (VII): 
wherein R2 is a hydroxy-protecting group; reacting the compound (VII) with acetyl halide under the conditions for Friedel-Crafts reaction to yield a compound of the formula (VIII): 
wherein R2 is a hydroxy-protecting group; and subjecting the compound (VIII) to oxidation of the acetyl group and optionally deprotection.
The present invention further provides a method for the preparation of the above-mentioned 5-hydroxybenzo[b]thiophene-3-carboxylic acid derivative of the general formula (VI) by using a compound of the formula (I). Thus, the present invention provides a process for preparing a compound of the formula (VI): 
wherein R is as defined above and X is hydrogen or alkyl, and double bond represents either E- or Z-configuration, or a pharmaceutically acceptable salt thereof or a hydrate thereof, which comprises subjecting a compound of the formula (I) or a reactive derivative thereof to the following reactions:
(1) reaction with a compound of the formula (V) 
wherein X is hydrogen or alkyl; or
(2) reaction with a compound of the formula (Vxe2x80x2): 
or a salt thereof followed by oxidation and reaction with an ylide under the conditions for Wittig reaction; and
(3) optionally deprotection.
The terms used herein are defined below.
The term xe2x80x9chydroxy-protecting groupxe2x80x9d means alkyl, alkoxyalkyl, acyl, aralkyl, alkylsulfonyl, arylsulfonyl, alkyl-substituted silyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or tetrahydropyranyl.
The term xe2x80x9calkylxe2x80x9d means C1-C20 linear or branched alkyl, particularly, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl and the like, and C1-C6 alkyl is preferred.
The term xe2x80x9calkoxyxe2x80x9d means C1-C6 linear or branched alkoxy, particularly, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, neopentyloxy, s-pentyloxy, t-pentyloxy, n-hexyloxy, neohexyloxy, i-hexyloxy, s-hexyloxy, t-hexyloxy and the like, and C1-C3 alkoxy is preferred.
The term xe2x80x9calkoxyalkylxe2x80x9d means alkyl group substituted by alkoxy group, including methoxymethyl, ethoxymethyl, methoxyethoxymethyl, ethoxyethyl, methoxypropyl and the like.
The term xe2x80x9cacylxe2x80x9d means C1-C11 acyl derived from aliphatic carboxylic acid or aromatic carboxylic acid. Examples of aliphatic carboxylic acid-derived acyl include acetyl, chloroacetyl, trichloroacetyl, propionyl, butyryl, valeryl and the like, and examples of aromatic carboxylic acid-derived acyl include benzoyl, p-nitrobenzoyl, p-methoxybenzoyl, p-bromobenzoyl, toluoyl, naphthoyl and the like.
The term xe2x80x9carylxe2x80x9d means phenyl, naphthyl or polycyclic aromatic hydrocarbon group and the like. In addition, aryl may be substituted by the following substituents.
Examples of substituent include alkyl such as methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or tert-pentyl, lower alkoxy such as methoxy or ethoxy, halogen such as fluoro, chloro, bromo or iodo, nitro, hydroxy, carboxy, cyano, sulfonyl, amino, lower alkylamino such as methylamino, dimethylamino, ethylmethylamino or diethylamino, and the like. The aryl group may have one or more substituents at any possible positions. Specific examples of aryl include 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 4-pentylphenyl, 4-carboxyphenyl, 4-acetylphenyl, 4-(N,N-dimethylamino)phenyl, 4-nitrophenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-iodophenyl and the like.
The aryl group in the xe2x80x9caralkylxe2x80x9d, xe2x80x9carylsulfonylxe2x80x9d, xe2x80x9caryloxycarbonylxe2x80x9d or xe2x80x9caralkyloxycarbonylxe2x80x9d described below may have similar substituents as defined above.
The term xe2x80x9caralkylxe2x80x9d means an alkyl group substituted by aryl group, and includes benzyl, 4-methylbenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, naphthylmethyl, phenethyl, and the like.
The term xe2x80x9calkylsulfonylxe2x80x9d means a sulfonyl group substituted by alkyl group, and includes methanesulfonyl, ethanesulfonyl and the like.
The term xe2x80x9carylsulfonylxe2x80x9d means a sulfonyl group substituted by aryl group, and includes benzenesulfonyl, p-toluenesulfonyl, and the like.
The term xe2x80x9calkyl-substituted silylxe2x80x9d means mono-, di- or tri-alkyl-substituted silyl, for example, methylsilyl, dimethylsilyl, trimethylsilyl, t-butyldimethylsilyl, and the like.
The term xe2x80x9calkoxycarbonylxe2x80x9d means methoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl, and the like.
The term xe2x80x9caryloxycarbonylxe2x80x9d means phenoxycarbonyl, and the like.
The term xe2x80x9caralkyloxycarbonylxe2x80x9d means benzyloxycarbonyl, and the like.
Although all the above-mentioned hydroxy-protecting groups are preferred as the hydroxy-protecting group shown by R1, R2 or R in respective formula above, aryl sulfonyl is more preferred and benzenesulfonyl is particularly preferred among them.
Examples of salts of the compound of the general formula (VI) include alkali metal salts such as lithium salt, sodium salt or potassium salt and the like, alkali earth metal salts such as calcium salt and the like, ammonium salt, salts with organic base such as tromethamine, trimethylamine, triethylamine, 2-aminobutane, tert-butylamine, diisopropylethylamine, n-butylmethylamine, n-butyldimethylamine, tri-n-butylamine, cyclohexylamine, dicyclohexylamine, N-isopropylcyclohexylamine, furfurylamine, benzylamine, methylbenzylamine, dibenzylamine, N,N-dimethylbenzylamine, 2-chlorobenzylamine, 4-methoxybenzylamine, 1-naphthalenemethylamine, diphenylbenzylamine, triphenylamine, 1-naphthylamine, 1-aminoanthracene, 2-aminoanthracene, dehydroabiethylamine, N-methylmorpholine or pyridine, or amino acid salts such as lysine salt or arginine salt.
The salts of the amino alcohol of the formula (Vxe2x80x2) include salts with organic acid such as benzoic acid, etc., and mineral acid such as hydrochloric acid, sulfuric acid, etc.
The final compound of the present invention is represented by the formula (VI) as described above, in which the double bond of the alkenylene side chain (5-heptenylene chain) may be in the E- or Z-configuration.
The method of the present invention is described below in more detail. When a substituent(s) possibly interfering the reaction is present, it can be appropriately protected and then deprotected at a desired stage. Such protection or deprotection can be accomplished by a procedure known in the art. 
Wherein R and R1 are as defined above.
[Step 1]
This step is related to the introduction of a propargyl group at the mercapto group of 4-mercaptophenol (1) and protection of hydroxyl group.
The introduction of a propargyl group is accomplished by using propargyl halide such as propargyl bromide, propargyl chloride and the like in the presence of a basic agents. The reaction can be accomplished within several tens minutes to several hours at room temperature by employing, as a basic agent, inorganic base such as potassium carbonate, sodium carbonate or the like, or an organic base such as triethylamine, pyridine, 4-dimethylaminopyridine or the like in a solvent such as acetone, ethyl acetate, tetrahydrofuran, acetonitrile, or the like.
When a strong base such as potassium hydroxide or sodium hydroxide is used, it can be also accomplished in a two-layer solvent system such as toluene-water or xylene-water.
The protection of hydroxyl group may be conducted using an ordinary hydroxy-protecting group in a conventional manner. Preferred protecting groups to be used in the present method are those which do not undergo changes during the oxidative reactions in the 2nd and 4th steps of the present Process and the 2nd step of Process IV below for the preparation of compound of the formula (VI) and also during the Wittig reaction of the 3rd step of said Process, and can be easily deprotected in the 4th step to give leaving groups which are easily separable from, for example, Compound A for purification thereof, which corresponds to a compound of the formula (VI) wherein OR is 5-hydroxy, X is hydrogen and double bond is in Z-configuration. Examples of such a hydroxy-protecting group include alkyl, alkoxyalkyl, acyl, aralkyl, alkylsulfonyl, arylsulfonyl, alkyl-substituted silyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or tetrahydropyranyl.
Considering the requirements that a protecting group should survive during the Wittig reaction conducted under strong basic conditions, be easily deprotected, for example, in the 4th step for the preparation of Compound A, and be separable from Compound A, arylsulfonyl is more preferred and benzenesulfonyl is particularly preferred. Benzenesulfonyl group is relatively stable to base in anhydrous solvents and, upon deprotection, gives benzenesulfonic acid which is water-soluble and is easily separated from the final product of the formula (VI). The protection and deprotection can be carried out by a method known in the art. For example, in the case of benzenesulfonyl group, the introduction of benzenesulfonyl group is carried out in a manner similar to that for the introduction of propargyl group by using benzenesulfonyl chloride.
[Step 2]
This step is related to oxidation of the compound (II).
There have been known oxidizing methods which use, for instance, aqueous hydrogen peroxidexe2x80x94acetic acid (J. Am, Chem. Soc., 87, 1109-1114 (1965)), aqueous hydrogen peroxidexe2x80x94titanium(III) chloride (Synthesis 1981, 204-206), m-chloroperbenzoic acid (Org. Synth., 64, 157-163 (1985)), or sodium metaperiodate (J. Org. Chem., 27, 282-284 (1962)).
In the present step, it is preferred to use a slightly excess amount of 30% aqueous hydrogen peroxide in an alcoholic solvent such as ethanol, methanol, isopropanol or tert-butanol solution containing formic acid. The reaction is accomplished within several tens minutes to several hours under cooling or at room temperature.
[Step 3]
This step is related to the conversion of the compound (III) into the hydroxymethyl compound (IV) by thermal rearrangement reaction. The thermal rearrangement reaction in this step is carried out according to the method described in J. C, S. Chem. Comm., 1974, 848-849. Examples of preferred solvents for this reaction include dioxane, 1,2-dimethoxyethane, propyl acetate and 3-pentanone. The reaction is accomplished by refluxing in a solvent for several hours followed by adding to the resultant intermediate an acid (p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, etc.) [Step 4]
This step is related to the oxidation of the compound (IV) to provide carboxylic acid (I). The oxidation can be carried out either directly or in a stepwise manner. Examples of oxidizing agent for converting an aromatic primary alcohol to the corresponding carboxylic acid directly include chromic acids (Synthesis. 1986, 285-288), potassium permanganate (J. Org. Chem., 18, 806-809 (1953)) and ruthenium oxides (J. C. S. Chem. Comm., 1979, 58-59)). However, these methods have disadvantages in not only the yield but also the following matters. For instance, the reaction time is long, the detoxification treatment of oxidizing agent is needed following the reaction, the reagents are unstable and/or they involve complicated operations.
On the contrary, in some cases, a stepwise oxidation wherein a primary alcohol is oxidized to an aldehyde and then to a carboxylic acid may be of advantage with regard to yield. In general, the oxidation of alcohol to aldehyde has been carried out by using an oxidizing agent of chromic acid series, for example, Jones reagents (J. Org. Chem., 40, 1664-1665 (1975)), Collins reagents (J. C. S. Chem. Comm., 1972 1126)), pyridinium chlorochromate (Tetrahedron Lett., 2647-2650 (1975)). It has been also known a method which uses manganese dioxide (Helv. Chim. Acta., 39, 858-862 (1956)) or dimethyl sulfoxide (Swern oxidation, J. Org. Chem., 43, 2480-2482 (1978)). However, these existing methods have disadvantages. For example, chromic acids are toxic to human body and must be detoxified after use. Further, the Swern oxidation using dimethyl sulfoxide-oxalyl chloride is not suited for a large scale production because it is accompanied by the generation of carbon monoxide harmful to workers and sulfurous odor and also it must be carried out at low temperature, for example, between xe2x88x9250xc2x0 C. and xe2x88x9278xc2x0 C.
Alcohol (IV) can be converted into aldehyde (IVxe2x80x2) almost quantitatively by a method wherein an alcohol (IV) is oxidized with an oxidizing reagent such as halo oxoacid in the presence of 2,2,6,6-tetramethylpiperidine-1-oxyl or the like (referred to as xe2x80x9cTEMPOsxe2x80x9d) according to the description in a literature (e.g., J. Org. Chem., 52, 2559-2562 (1987)), whereby the problems of the existing methods are solved. Examples of TEMPOs usable include 2,2,6,6-tetramethylpiperidine-1-oxyl, 4-methoxy-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-benzoyloxy-2,2,6,6-tetramethylpiperidine-1-oxyl, and 4-cyano-2,2,6,6-tetramethylpiperidine-1-oxyl. Examples of usable halo oxoacids include sodium hypochlorite, sodium hypobromite, sodium bromite and higher bleaching powder. A solution of an oxidizing agent may be adjusted to, for example, pH 8.5 to 9.5 with a mineral acid such as sodium hydrogen carbonate, hydrogen chloride or sulfuric acid. Alternatively, a solution of an oxidizing agent may be added in the presence of sodium hydrogen carbonate. The reaction can be accomplished within several minutes to several tens minutes at temperature from ice-cooling to room temperature in a solvent such as ethyl acetate, acetonitrile or dichloromethane.
When the reaction solution containing the resultant aldehyde (IVxe2x80x2) is acidified and sodium chlorite and aqueous hydrogen peroxide are added thereto, the aldehyde is converted into carboxylic acid under ice-cooling within several tens minutes to several hours.
If desired, the product may be further subjected to the deprotection of 5-hydroxy-protecting group and/or conversion into reactive derivatives at 3-carboxyl group. Such xe2x80x9creactive derivativexe2x80x9d includes the corresponding acid halides (e.g., chloride, bromide, iodide), acid anhydrides (e.g., mixed acid anhydride with formic acid or acetic acid), activated esters (e.g., succinimide ester), and the like, and includes acylating agents generally used for the acylation of amino group. For example, to obtain acid halides, a carboxylic acid is reacted with thionyl halide (e.g., thionyl chloride), phosphorous halide (e.g., phosphorous trichloride, phosphorous pentachloride), oxalyl halide (e.g., oxalyl chloride), or the like, according to a known method (e.g., Shin-jikken Kagaku Koza, vol. 14, p. 1787 (1978); Synthesis 852-854(1986); Shin-jikken Kagaku Koza vol. 22, p. 115 (1992)). 
wherein R and R2 are as defined above.
[Step 1]
This step is related to the protection of 5-hydroxy group of compound (7).
The compound (7) as the starting material of the present step is known in a literature (J. Am. Chem. Soc., 57, 1611-1616 (1935), Ann. Chem., 527, 83-114 (1938), J. Am. Chem. Soc., 78, 5351-5357 (1956), J. Org. Chem., 41, 1118-1124 (1976)). The hydroxyl group of this compound is protected appropriately in a manner similar to that described in the 1st step of Process I above. For example, when benzenesulfonyl group is used, the compound is added to benzenesulfonyl chloride in the presence of an inorganic base such as sodium carbonate or potassium carbonate, or an organic base such as triethylamine or tripropylamine. Example of preferred solvent includes acetone, ethyl acetate and tetrahydrofuran. The reaction is accomplished within several minutes to several hours at temperature from room temperature to the boiling point of the solvent. The compound (VII) can be also synthesized by a broadly used method, commonly known as xe2x80x9cSchotten-Baumann reactionxe2x80x9d.
[Step 2]
This step is related to the introduction of acetyl group to the 3-position of the compound (VII) by Friedel-Crafts reaction. The introduction of acetyl group is, for example, carried out using acetyl chloride or acetyl bromide in the presence of a catalyst, for example, a Lewis acid such as aluminium chloride, ferric chloride, zinc chloride, tin chloride and boron trifluoride. Example of usable solvent includes carbon disulfide, nitrobenzene or a halogenated hydrocarbons such as methylene chloride or ethylene chloride. The reaction is in general accomplished within several hours at temperature of ice-cooling to room temperature. The 2-acetyl compound slightly produced as a by-product is easily separable by recrystallization.
[Step 3]
This step is related to the conversion of the compound (VIII) into a carboxylic acid (I) or a reactive derivative thereof through the oxidation of the acetyl group in the presence of a salt of hypohalous acid. Examples of preferred hypohalogenite include alkali metal or alkaline earth metal salts of hypohalous acids, and potassium, sodium or calcium salt of hypochlorous or hypobromous acid is especially preferred.
In an aqueous solution of such a salt, the oxidation progresses at relatively low temperature. However, dioxane or 1,2-dimethoxyethane may be used as a solvent so as to increase the solubility of the compound to be oxidized. The reaction is accomplished within several hours to several tens hours at room temperature or with heating. 
wherein R and X are as defined above and the double bond represents E- or Z-configuration.
This process is related to the synthesis of a compound of the formula (VI) by reacting a compound of the formula (I) or a reactive derivative thereof obtained in Process I or II above with a compound of the formula (V).
The compound (V) used in the present process is obtainable according to the method described in Japanese Patent Publication (KOKOKU) No. 6-23170 (23170/1994).
The reaction can be carried out under ordinary conditions for acylation of amino group. For example, when a carboxylic acid halide is used, the reaction is carried out according to a method commonly known as xe2x80x9cSchotten-Baumann reactionxe2x80x9d. In general, carboxylic acid halide is added dropwise to an aqueous alkaline solution of amine with stirring and under cooling while removing the generating acid with alkali. Alternatively, when a carboxylic acid is used as a free acid not a reactive derivative, the reaction can be conducted conventionally in the presence of a coupling agent generally used in the coupling reaction between an amine and a carboxylic acid such as dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide or N,Nxe2x80x2-carbonyldiimidazole. 
wherein R and X are as defined above and the double bond represents E- or Z-configuration.
[Step 1]
This step is related to the preparation of a compound of the formula (IX) by reacting a compound of the formula (I) or a reactive derivative thereof with a compound of the formula (Vxe2x80x2) or its salt in a manner similar to that described in Process III above. The preparation of some of the compounds of the formula (VI) is described in Chem. Pharm. Bull. Vol.37, No. 6 1524-1533 (1989).
[Step 2]
This step is related to the preparation of an aldehyde of the formula (X) by oxidizing a compound of the formula (IX). The reaction can be carried out for several hours under cooling or at room temperature using an oxidizing agent selected from chromic acid series such as Jones reagents, Collins reagents, pyridinium chlorochromate, pyridinium dichromate or dimethyl sulfoxide-oxalyl chloride in a solvent such as chlorinated hydrocarbons (chloroform, dichloromethane, etc.), ethers (ethyl ether, tetrahydrofuran, etc.), acetone or benzene.
[Step 3]
This step is related to the formation of a double bond by reacting a compound of the formula (X) with an ylide (Ph3Pxe2x95x90CH(CH2)3COOH). The reaction for providing a double bond can be carried out in a conventional manner for Wittig reaction. The ylides used in the reaction can be synthesized, in the presence of a base, by treating a phosphonium salt which has been synthesized from triphenylphosphine and an alkyl halide having a desired alkyl group to be condensed, for example, 5-bromopentanoic acid. Examples of a base include dimsyl sodium, dimsyl potassium, sodium hydride, n-butyl lithium, potassium t-butoxide and lithium diisopropylamide. The reaction is accomplished within several hours at room temperature in a solvent such as ether, tetrahydrofuran, n-hexane, 1,2-dimethoxyethane or dimethyl sulfoxide.
[Step 4]
In this step, a compound (VI) wherein R is hydroxy-protecting group is optionally deprotected to give compound (VI-1). The reaction can be carried out in a conventional manner using a catalyst such as hydrochloric acid, sulfuric acid, sodium hydroxide, potassium hydroxide or barium hydroxide, or the like. The reaction is accomplished within several tens minutes to several hours with heating in a solvent such as methanol-water, ethanol-water, acetone-water, acetonitrile-water, or the like, preferably dimethyl sulfoxide-water.